Immunodeficiency 78 with autoimmunity and developmental delay

Summary

Immunodeficiency 78 with autoimmunity and developmental delay (MONDO:0030971) is a disease caused by TPP2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TPP2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 78 with autoimmunity and developmental delay
Mondo ID	MONDO:0030971
OMIM	619220
UMLS	C5543159
MedGen	1785772
Is cancer (heuristic)	no

Also known as: IMD78 · immunodeficiency 78 with autoimmunity and developmental delay · TPP2 deficiency

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 78 with autoimmunity and developmental delay

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 pathogenic, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027537	NM_001330588.2(TPP2):c.2343C>G (p.Tyr781Ter)	TPP2	Pathogenic	no assertion criteria provided
1027538	NM_001330588.2(TPP2):c.1499G>A (p.Gly500Asp)	TPP2	Pathogenic	no assertion criteria provided
1027539	NM_001330588.2(TPP2):c.433del (p.Ala145fs)	TPP2	Pathogenic	no assertion criteria provided
995805	NM_001330588.2(TPP2):c.2394-550_2952+659del	TPP2	Pathogenic	no assertion criteria provided
4292206	NM_001330588.2(TPP2):c.3012del (p.Tyr1005fs)	TPP2	Likely pathogenic	criteria provided, single submitter
1027541	NM_001330588.2(TPP2):c.82T>G (p.Cys28Gly)	TPP2	Uncertain significance	criteria provided, single submitter
1046445	NM_001330588.2(TPP2):c.3461A>C (p.Gln1154Pro)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675145	NM_001330588.2(TPP2):c.3136A>G (p.Met1046Val)	TPP2	Uncertain significance	criteria provided, single submitter
2437220	NM_001330588.2(TPP2):c.2137C>A (p.Pro713Thr)	TPP2	Uncertain significance	criteria provided, single submitter
640880	NM_001330588.2(TPP2):c.2237T>A (p.Ile746Asn)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
662393	NM_001330588.2(TPP2):c.3074A>G (p.Glu1025Gly)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
847645	NM_001330588.2(TPP2):c.2027C>T (p.Thr676Ile)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
857859	NM_001330588.2(TPP2):c.2402G>A (p.Ser801Asn)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
949468	NM_001330588.2(TPP2):c.1270A>G (p.Ile424Val)	TPP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1618132	NM_001330588.2(TPP2):c.1016+17A>G	TPP2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TPP2	Definitive	Autosomal recessive	immunodeficiency 78 with autoimmunity and developmental delay	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPP2	Orphanet:444463	Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome due to TPP2 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPP2	HGNC:12016	ENSG00000134900	P29144	Tripeptidyl-peptidase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPP2	Tripeptidyl-peptidase 2	Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPP2	Protease	yes	3.4.14.10	Peptidase_S8/S53_dom, Peptidase_S8_subtilisin-rel, TPPII_Ig-like-2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPP2	286	ubiquitous	marker	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPP2	1,967

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPP2	P29144	91.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	TPP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular amino acid homeostasis	1	5617.3×	5e-04	TPP2
protein polyubiquitination	1	115.4×	0.013	TPP2
proteolysis	1	34.2×	0.029	TPP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPP2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	TPP2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TPP2	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPP2	3.4.14.10	tripeptidyl-peptidase II

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	TPP2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TPP2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.